From barbiturates to ganaxolone: The importance of chirality in drug development and in understanding the actions of old and new antiseizure medications

Review

Author: Bialer, Meir ; Perucca, Emilio

Out of 37 antiseizure medications (ASMs) currently in the market, 17 are chiral molecules and an additional one (oxcarbazepine) is a prodrug of the chiral compound licarbazepine. Of the 17 chiral ASMs, six (ethosuximide, fenfluramine, methsuximide, mephobarbital, stiripentol and vigabatrin) are marketed as racemates, and the remainder are licensed as enantiomerically pure medicines. Of note, all chiral ASMs introduced prior to 1990 were marketed as racemates. Stiripentol, fenfluramine and vigabatrin are the only racemic ASMs approved by the FDA >10 years after the release of regulatory guidelines on the development of chiral medicines. Despite the fact that pharmacokinetic and pharmacodynamic differences between enantiomers have been recognized for decades, the importance of chirality in understanding the biological actions of ASMs is not widely appreciated, and many recent publications on racemic ASMs refer to these medications as if they were a single molecular entity. In the present article, we provide a critical review of chiral ASMs developed between the 1920s, when mephobarbital was introduced, and 2022, when the last chiral ASM (ganaxolone) was approved. We summarize available data on stereoselective differences in pharmacokinetics and pharmacodynamics of ASMs marketed as racemates. We also discuss regulatory aspects related to the introduction of racemic medicines within the current regulatory scenario in Europe and the U.S., focusing on stiripentol, vigabatrin and fenfluramine as examples of different approaches. We identified a number of critical knowledge gaps that are relevant to the use of chiral drugs in epilepsy, including a remarkable lack of published information on the comparative pharmacokinetics, toxicity and antiseizure activity of the enantiomers of most racemic ASMs. The importance of chirality aspects in understanding the clinical actions of racemic ASMs is discussed, together with the rationale for the development of enantiomerically pure follow-up compounds with potentially improved efficacy, safety and commercial viability.

01 Jan 2024·Methods in Molecular Biology

Analysis of Barbiturates in Urine by LC-MS/MS

Article

Author: Horne, Hunter ; Janis, Gregory ; Campbell, Matthew ; Ketha, Hemamalini

In the method described here, an aliquot of a urine sample is analyzed to detect barbiturates through dilution and ultra-high-performance chromatography-tandem mass spectrometry (UPLC-MS/MS) using deuterated internal standards. This assay detects the presence of nine barbiturate drugs-amobarbital, barbital, butalbital, butabarbital, mephobarbital, secobarbital, pentobarbital, phenobarbital, and thiopental. This protocol describes two LC separation methods-first LC method (2.2 min/sample) is intended to be used as a first step of the analysis that does not separate amobarbital and pentobarbital, and a second, longer (2.7 min/sample) LC method is intended to be used only for samples which have a peak in the amobarbital/pentobarbital retention time on the shorter LC method. Since the frequency at which amobarbital and pentobarbital are observed in clinical populations is low, the shorter LC method helps gain efficiency in a high-volume laboratory environment. Additional features of this protocol that help in efficiency gain are automated extraction using Hamilton™ liquid handling system and algorithmic data review using Ascent™ software.

01 May 2023·Journal of Pharmaceutical and Biomedical Analysis

New approach for barbiturates, phenytoin, methyprylon and glutethimide determination and fragmentation (UHPLC-MS/MS)

Article

Author: Tusiewicz, Kaja ; Zawadzki, Marcin ; Wachełko, Olga ; Szpot, Paweł

Barbiturates which are old pharmaceutical drugs are still widely used in medical treatment of epilepsy and for general anesthesia. To date, more than 2500 different barbituric acid analogs have been synthesized, and 50 of them were introduced into medical use over the last century. Due to their highly addictive properties, pharmaceuticals containing barbiturates are under strict control in many countries. However, by considering the worldwide problem with new psychoactive substances (NPS) the introduction of new designer barbiturate analogs into the dark market might serve a serious public health problem in the near future. For this reason there is an increasing need for application methods for barbiturates monitoring in biological samples. The UHPLC-QqQ-MS/MS method for determination of 15 barbiturates, phenytoin, methyprylon and glutethimide was developed and fully validated. The biological sample volume was reduced to only 50 µL. A simple LLE (pH 3 with ethyl acetate) was successfully applied. The lower LOQ was 10 ng/mL. The method enables differentiation of structural isomers: hexobarbital and cyclobarbital; as well as amobarbital and pentobarbital. Chromatographic separation was achieved with the use of the alkaline mobile phase (pH 9) and Acquity UPLC BEH C18 column. Furthermore, the novel fragmentation mechanism of barbiturates was proposed, which may have a great impact in identification of novel barbiturates analogs introduced to illegal marketplaces. The presented technique has a great potential to be applied in forensic, clinical and veterinary toxicological laboratories, as was evidenced by the positive results of international proficiency tests.

100 Deals associated with Methylphenobarbital

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KEGG	Wiki	ATC	Drug Bank
-	Methylphenobarbital	N03AA01	DB00849

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Indication	Country/Location	Organization	Date
Epilepsy	-	-	-
Sedation	-	-	-

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